Telomeres are specialized DNA sequences at the end of each chromosome. Telomere length shortens progressively during each round of cell cycle and declines with aging, and thus has emerged as a valuable biomarker for biological aging and age-related disorders. Shorter telomeres have been associated with increased risk for type 2 diabetes and its related phenotypes. These associations, however, were primarily based on cross-sectional data, and therefore raise an important question as to whether shorter telomeres are a cause or a consequence of diabetes, or whether it is simply an epiphenomenon. Diabetes disproportionately affects American Indians. The prevalence of type 2 diabetes is, on average, 2-4 times higher than that in other ethnic groups. The objectives of this study are to delineate the prospective impact of telomere attrition on diabetes risk, and to determine genetic, behavioral and psychosocial predictors for accelerated telomere loss. Leukocyte telomere length will be measured by quantitative PCR in 4,565 DNA samples collected by the Strong Heart Family Study at two clinical visits (900 subjects examined at both visits, 2,765 examined at the second visit only). All DNA samples, well-characterized clinical data including follow-up data through December 2009 and data from a 10cM genome scan are already available for the proposed analyses. Specific aims: 1) To determine whether telomere attrition is associated with diabetes and its related phenotypes; 2) To identify genetic loci related to telomeric variation by a genome-wide linkage scan; 3) To determine behavioral, socioeconomic and psychosomatic predictors for accelerated telomere shortening in relation to diabetes risk. This is the first study to investigate prospectively the associations of telomere length and of telomere attrition rate with diabetes risk, and is also the first study to determine genetic, behavioral and psychosocial predictors for accelerated telomere erosion in this underserved population. If the proposed aims are achieved, we will be able to provide valuable information regarding a causal role of accelerated telomere loss in the pathogenesis of diabetes, thereby providing evidence for telomere length as a biomarker for diabetes and its associated disorders. The results will also provide important information for risk stratification in American Indians and other ethnic groups as well. Furthermore, this study will provide valuable information for lifestyle/behavioral interventions for diabetic risk reduction. We expect that this study will open new lines of research, and could potentially lead to critical discoveries that will accelerate the field of aging and diabetes as well as a wide range of metabolic disorders, and thus is of great significance. PUBLIC HEALTH RELEVANCE: This study proposes to investigate the prospective association and determinants of telomere attrition and diabetes risk in American Indians using an existing, well-defined, longitudinal cohort, the Strong Heart Family Study. Results will provide valuable data regarding biological aging and diabetes in American Indians and other ethnic groups as well.